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A5271

Collection of Comparison Neurocognitive Data in Resource-Limited Settings

A Limited-Center Trial of the AIDS Clinical Trials Group (ACTG)

Sponsored by:

The National Institute of Allergyand Infectious Diseases

andThe National Institute of Mental Health

Non-IND Protocol

The ACTG Optimization of Co-Infection and Co-Morbidity Management (OpMAN) Committee: Thomas Campbell, M.D., Chair

The Neurology Subcommittee of OpMAN: Giovanni Schifitto, M.D., Chair

Protocol Chair: Kevin Robertson, Ph.D.

Protocol Vice Chair: Jeffery Schouten, M.D., J.D.

DAIDS Clinical Representative: Elizabeth Smith, M.D.

Clinical Trials Specialist: Sean McCarthy, R.N., M.S.

FINAL Version 1.0June 1, 2010

A5271FINAL Version 1.0

06/01/10

CONTENTS

Page

SITES PARTICIPATING IN THE STUDY......................................................................................4PROTOCOL TEAM ROSTER........................................................................................................5STUDY MANAGEMENT................................................................................................................8GLOSSARY OF TERMS.............................................................................................................10SCHEMA......................................................................................................................................11

1.0 HYPOTHESIS AND STUDY OBJECTIVES.........................................................121.1 Hypothesis...........................................................................................................121.2 Primary Objective.................................................................................................121.3 Secondary Objectives..........................................................................................12

2.0 INTRODUCTION..................................................................................................122.1 Background..........................................................................................................122.2 Rationale..............................................................................................................13

3.0 STUDY DESIGN..................................................................................................14

4.0 SELECTION AND ENROLLMENT OF PARTICIPANTS.....................................144.1 Step 1: Inclusion Criteria.....................................................................................144.2 Step 1: Exclusion Criteria....................................................................................154.3 Step 2: Inclusion Criteria.....................................................................................154.4 Step 2: Exclusion Criteria....................................................................................164.5 Participant Recruitment........................................................................................164.6 Study Enrollment Procedures..............................................................................164.7 Coenrollment........................................................................................................18

5.0 STUDY TREATMENT..........................................................................................18

6.0 CLINICAL AND LABORATORY EVALUATIONS.................................................196.1 Schedule of Events (SOE)...................................................................................196.2 Timing of Evaluations...........................................................................................196.3 Instructions for Evaluations..................................................................................20

7.0 CLINICAL MANAGEMENT ISSUES....................................................................24

8.0 CRITERIA FOR DISCONTINUATION.................................................................248.1 Premature Study Discontinuation.........................................................................24

9.0 STATISTICAL CONSIDERATIONS.....................................................................259.1 General Design Issues.........................................................................................259.2 Endpoints.............................................................................................................259.3 Registration and Stratification..............................................................................26

A5271FINAL Version 1.0

06/01/10CONTENTS (Cont’d)

Page

9.4 Sample Size and Accrual.....................................................................................269.5 Monitoring............................................................................................................279.6 Analyses...............................................................................................................27

10.0 PHARMACOLOGY PLAN....................................................................................28

11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING2811.1 Records to Be Kept..............................................................................................2811.2 Role of Data Management...................................................................................2811.3 Clinical Site Monitoring and Record Availability...................................................2811.4 Expedited Adverse Event Reporting to DAIDS....................................................28

12.0 HUMAN SUBJECTS............................................................................................2812.1 Institutional Review Board (IRB) Review and Informed Consent.........................2812.2 Participant Confidentiality.....................................................................................2912.3 Study Discontinuation..........................................................................................29

13.0 PUBLICATION OF RESEARCH FINDINGS........................................................29

14.0 BIOHAZARD CONTAINMENT.............................................................................29

15.0 REFERENCES.....................................................................................................30

APPENDIX I SAMPLE INFORMED CONSENT

4 A5271FINAL Version 1.0

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SITES PARTICIPATING IN THE STUDY

The following non-U.S. ACTG clinical research sites may participate in A5271:

Rio de Janeiro, Brazil (12101)Chennai, India (11701)

Pune, India (11601)Blantyre, Malawi (30301)Lilongwe, Malawi (12001)

Lima, Peru (11301 and 11302, enrolling as one site)Johannesburg, South Africa (11101)

Durban, South Africa (11201)Chiang Mai, Thailand (11501)

Harare, Zimbabwe (30313)


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PROTOCOL TEAM ROSTER

ChairKevin Robertson, Ph.D. Neurology, School of Medicine University of North Carolina at Chapel Hill 2127 Physicians Office Bldg, CB7025170 Manning DriveChapel Hill, NC 27599-7025Phone:(919) 966-5522Fax: (919) 966-2922E-mail: [email protected]

Vice ChairJeffrey T. Schouten, M.D., J.D.University of Washington 1100 Fairview Avenue N., LE-500Seattle, WA 98109-1024Phone:(206) 667-5980Fax: (206) 667-6366E-Mail: [email protected]

DAIDS Clinical Representative Elizabeth Smith, M.D.HIV Research Branch DAIDS, NIAID, NIH 6700-B Rockledge Drive, MSC 7624 Bethesda, MD 20892-7624Phone: (301) 402-3226Fax: (301) 480-4563E-mail: [email protected]

Clinical Trials SpecialistSean McCarthy, R.N., M.S.ACTG Operations CenterSocial & Scientific Systems8757 Georgia Avenue, 12th FloorSilver Spring, MD 20910-3714Phone:(301) 628-3394Fax: (301) 628-3302E-Mail: [email protected]

StatisticiansScott Evans, Ph.D.Statistical & Data Analysis Center Harvard School of Public Health Complications of HIV, Adult Division FXB Building, Room 513 651 Huntington Avenue Boston, MA 02115-6017Phone:(617) 432-2998Fax: (617) 432-3163E-mail: [email protected]

Jeanne Jiang, M.S.SDAC/Harvard School of Public Health Center for Biostatistics in AIDS Research FXB 549, 651 Huntington Avenue Boston, MA 02115Phone:(617) 432-6685Fax: (617) 432-3163E-mail: [email protected]

Data ManagersAnn Walawander, M.A. Frontier Science & Technology ResearchFoundation4033 Maple RoadAmherst, NY 14226-1056Phone:(716) 834-0900 x7290Fax: (716) 834-8432E-mail: [email protected]

Apsara Nair, M.S.Frontier Science & Technology ResearchFoundation4033 Maple RoadAmherst, NY 14226-1056Phone: (716) 834-0900 X7293Fax: (716) 834-8432E-mail: [email protected]

mailto:[email protected]









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InvestigatorsThomas B. Campbell, M.D. University of Colorado DenverMail Stop B-168, Room P15-1100112700 E. 19th AvenueAurora, CO 80045Phone:(303)724-4929Fax: (303) 724-4926E-mail: [email protected]

James G. Hakim, M.D.University of Zimbabwe - Parirenyatwa 10 Routeledge Milton Park HarareZIMBABWEPhone: 011 263 4 705986Fax: 011 263 470-4897E-mail: [email protected]

Christina M. Marra, M.D.University of Washington Harborview Medical Center Department of Neurology Box 359775 325 9th Avenue Seattle, WA 98104-2499Phone: (206) 897-5400Fax: (206) 341-5401E-mail: [email protected]

Ned Sacktor, M.D.Johns Hopkins University Johns Hopkins Bayview Medical Center Department of Neurology 4940 Eastern Avenue B Building, Room 123 Baltimore, MD 21224-2780Phone:(410) 550-0978Fax: (410) 550-0539E-mail: [email protected]

Investigators (cont’d)Marcus Tulius T Silva, M.D., Ph.D. Instituto de Pesquisa Clinica Evandro Chagas - IPECFundação Oswaldo Cruz - FIOCRUZ Avenida Brasil 4365 Manguinhos Rio de Janeiro 21040- 900BRAZIL Phone:011 55 21 3865 9595 Fax: 011 55 21 25644933 E-mail: [email protected] Field RepresentativesBaiba Berzins, M.P.H. Division of Infectious DiseasesNorthwestern University Medical School676 North St. Clair, Suite 200Chicago, IL 60611-3015Phone: (312) 695-5012Fax: (312) 695-5048E-mail: [email protected]

Beverly Putnam, R.N., M.S.NUniversity of Colorado DenverColorado ACTU Academic Office 1, MS8205Room L15-751912631 E. 17th AvenueAurora, CO 80045Phone:(303) 724-0762Fax: (303) 724-0802E-mail: [email protected]

Laboratory TechnologistDaniel EggersMassachusetts General Hospital AIDS Clinical Trials Group Lab 1 65 Landsdowne Street 4th floor, Room 435 Cambridge, MA 02139Phone:(617) 768-8374Fax: (617) 768-8299E-mail: [email protected]










06/01/10PROTOCOL TEAM ROSTER (Cont'd)

CSS RepresentativeMartha Tholanah Mensah-KingCAB Member 912 Ringwood Drive Strathven HarareZIMBABWEE-mail: [email protected]

International Program Specialist Christina Blanchard-Horan, Ph.DACTG Operations Center Social & Scientific Systems, Inc. 8757 Georgia Avenue Silver Spring, MD 20910Phone:(301) 628-3339Fax: (301) 628-3302E-mail: [email protected]

NIMH RepresentativePim Brouwers, Ph.D.NIMH ExtramuralCenter for Mental Health on AIDS 6001 Executive Boulevard, NSC Room 6216 Rockville, MD 20892-9619Phone:(301) 443-4526Fax: (301) 443-9719E-mail: [email protected]





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STUDY MANAGEMENT

All questions concerning this protocol should be sent to [email protected] via e-mail. The appropriate team member will respond with a "cc" to [email protected]. A response should generally be received within 24 hours (Monday-Friday).

Protocol E-mail GroupSites registering to this study must contact the Computer Support Group at the Data Management Center (DMC) to have the relevant personnel at the site added to the actg.protA5271 email group. Include the protocol number in the email subject line.

Send an e-mail message to [email protected]

Clinical Management For questions concerning entry criteria and coenrollment, contact the protocol chair via an e-mail message to [email protected] (ATTN: Kevin Robertson, Ph.D.). Include the protocol number, patient identification number (PID), and a brief relevant history

Data ManagementFor nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), the CRF schedule of events, registration, and other data management issues, contact the data managers. For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact the

protocol data managers: Ann Walawander and Apsara Nair directly ([email protected] and [email protected]).

For other questions, send an e-mail message to [email protected] (ATTN: Ann Walawander and Apsara Nair).

Include the protocol number, PID, and a detailed question.

Participant Registration For questions or problems and study identification number (SID) lists: Send an e-mail message to [email protected] or

call the Statistical and Data Analysis Center (SDAC)/DMC Randomization Desk at (716) 898-7301.

Computer and Screen Problems Contact the SDAC/DMC programmers. Send an e-mail message to [email protected] or call (716) 834-0900 x7302.

Protocol Document QuestionsFor questions concerning the protocol document, contact the clinical trials specialist. Send an e-mail message to [email protected] (ATTN: Sean McCarthy).

Copies of the ProtocolTo request hard copies of the protocol, send a message to [email protected] . (ATTN: Diane Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site (https://www.actgnetwork.org ).

https://www.actgnetwork.org/




mailto:%[email protected]








06/01/10STUDY MANAGEMENT (Cont'd)

Protocol RegistrationFor protocol registration questions: Send an e-mail message to [email protected] or call (301) 897-1707.

Phone CallsAny phone calls must be documented by e-mail to [email protected]. This will be the site’s responsibility.

Protocol-Specific Web PageAdditional information concerning study management of ACTG studies can be found on the ACTG Web page.




06/01/10GLOSSARY OF TERMS

AIDS Acquired immunodeficiency syndromeADL Activities of daily livingBMI Body mass indexCNS Central nervous systemCRF Case report formCRS Clinical research sitesDAIDS Division of AIDSDMC Data Management CenterEC Ethics committeeEIA Enzyme immunoassayELISA Enzyme-linked immunosorbent assayHAART Highly active antiretroviral therapyHAD HIV-associated dementiaHAND HIV-Associated Neurological DisordersHIV-1 Human immunodeficiency virus type 1HIV-1 RNA HIV Viral loadHVTL-R Hopkins Verbal Learning Test – RevisedIATA International Air Transport AssociationIRB Institutional review boardIHDS International HIV Dementia ScaleMOPS Manual of OperationsMND Minor neurocognitive disorderNIAID National Institute of Allergy and Infectious DiseasesNIH National Institutes of HealthNIMH National Institute of Mental HealthOHRP Office for Human Research ProtectionsPID Patient/participant identifier (number)PNS Peripheral nervous systemRSC Regulatory Support CenterSD Standard deviationSDAC Statistical and Data Analysis CenterSID Study identification numberSIP Site Implementation PlanSOE Schedule of EventsVCT Voluntary counseling and testing


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SCHEMA

A5271

Collection of Comparison Neurocognitive Data in Resource-Limited Settings

DESIGN A two-step prospective, observational, multinational study to collect comparative neurocognitive data for application to other studies. Neurologically healthy HIV-seronegative individuals from resource-limited settings will be enrolled. Participants will have a baseline neuropsychological assessment performed, and a subset of participants will have a second visit in 6 months.

DURATION One day for the 1600 participants who do not enter Step 2; 6 months for 800 Step 2 participants.

SAMPLE SIZE 2400 men and women ≥ 18 years of age.

POPULATION All participants will be determined as neurologically healthy HIV-seronegative individuals on the basis of a detailed medical history.

STRATIFICATION Eighty (80) strata will be utilized, defined by site (10 levels), sex (2 levels), age (2 levels), and years of education (2 levels). Each of 10 sites will enroll 30 participants in each of eight strata as defined below:

Male, age <35 years, <10 years of education Male, age <35 years, ≥ 10 years of education Male, age ≥35 years, <10 years of education Male, age ≥35 years, ≥ 10 years of education Female, age <35 years, <10 years of education Female, age <35 years, ≥ 10 years of education Female, age ≥35 years, <10 years of education Female, age ≥35 years, ≥ 10 years of education

STEP 1 At Step 1, study participants will be offered the option of asingle 6-month follow-up visit.

STEP 2 Participants who have elected to complete a follow-up visit (800 total participants comprising 10 from each stratum) will be registered to Step 2 and return for a second/final study visit in 6 months.


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1.0 HYPOTHESIS AND STUDY OBJECTIVES

1.1 Hypothesis

Data from this study will aid in the interpretation of neurocognitive data from other studies collecting neurocognitive data in these settings. No hypothesis is being tested.

1.2 Primary Objective

To collect comparative neuropsychological data in healthy controls to aid in the interpretation of neuropsychological tests in resource-limited settings.

1.3 Secondary Objectives

1.3.1 To describe the distribution of neuropsychological scores in neurologically healthy HIV-seronegative individuals in resource-limited settings.

1.3.2 To estimate practice/learning effects associated with repeated neuropsychological assessment in resource-limited settings.

2.0 INTRODUCTION

2.1 Background

The global burden of the HIV epidemic is staggering, but in the short term, it is largely unfelt in the developed world. Ninety-five percent of new infections occur in the developing world [1]. From the early stages of the HIV epidemic in the United States, it has been recognized that central and peripheral nervous systems (CNS and PNS) are affected by HIV. The exact mechanism of neurotoxicity is not established, as there is no compelling evidence of productive infection of neurons. There is considerable evidence to suggest that local changes in immune and inflammatory activity in the CNS and PNS are responsible for this neurotoxicity.

Initial reports indicated that as many as 40% of infected patients developed a dementing disease. This dementing illness appeared to be due to HIV infection of the CNS, and not to one of many CNS opportunistic infections. The spectrum of primary HIV neurological diseases has been given the name HIV-associated neurological disorders (HAND). HAND includes the more severe form of HIV-associated dementia (HAD). Many more patients have evidence of less severe nervous system dysfunction, which has been termed HIV-associated minor neurocognitive disorder (MND). These disorders were previously known as AIDS dementia complex and minor cognitive/motor disorder, respectively [2-6]. In the pre-highly active antiretroviral therapy (HAART) era, in the United States, as many as 80% who died from AIDS had autopsy evidence of CNS injury attributable to HIV regardless of whether there had been manifestations of HAD during life [7].

HIV-associated cognitive impairment is associated with substantial impact on even the


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simplest activities of daily living. Differentiation between the milder form, MND, and the more severe, HAD, depends in part on the severity of the impact on daily functioning and activities. Although not well understood and researched, there have been initial studies quantifying the relationship between HIV-related neurological disease and quality of life. The burden of neurological disease on families and communities is substantial, with an impact in terms of loss of productivity and income for the person diagnosed as well as for those who take the primary responsibility as caretakers. In resource-limited settings with high rates of HIV-infection the toll is likely devastating, but remains to be documented [8, 9].

In the developed world, cognitive impairment is relatively common in HIV-infected individuals who have not been treated with antiretroviral therapy [5]. Most HIV-infected individuals in resource-limited settings have not been on an antiretroviral regimen and are likely to be at the same or greater risk for HAD than their infected counterparts with access to HAART in the developed world. Neuropsychological assessment is sensitive and specific for HIV-1-related cognitive dysfunction [10,11].

Very little is known about the prevalence of HAD and milder neuropsychological dysfunction in HIV-infected people in resource-limited settings. Resource-limited communities in sub-Saharan Africa, Asia, and the rest of the developing world, however, represent the areas most devastated by the HIV epidemic and stand to gain the most from effective therapy.

Neuropsychological assessment is arguably the most important tool for diagnosing and categorizing HIV effects on the CNS. Especially in resource-limited settings, where sophisticated technology is often unavailable, characterization of neurocognitive functioning through neuropsychological assessments is crucial to successful diagnosis and treatment. When appropriate normative standards exist, neuropsychological assessments are sensitive to HIV-related neurocognitive disorders and provide accurate ratings of impairment.

In order to appropriately interpret and provide a standardized approach to rating neurocognitive assessments, comparison data in healthy controls is needed. The accumulation of appropriate normative data that will allow more accurate rating of neuropsychological test performance will be crucial to future efforts at identifying neurocognitive impairment directly attributable to HIV; exploring relationships between HIV-associated neurocognitive impairment, disease variables, and everyday functioning; evaluating differences in HIV-1 subtype-associated neuropathology; and determining implications for treatment.

2.2 Rationale

Recent scientific discussion has resulted in recommendations to collect appropriate normative comparison data in resource-limited settings [12-15] to aid in the interpretation of neurocognitive data collected in these settings [16-18]. A recent National Institute of Mental Health (NIMH)-sponsored conference has recommended collection of normative data in studies examining neurocognitive functioning in resource-limited settings [19].


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Currently, comparative data on healthy controls does not exist in resource-limited settings. This limits the ability to (1) assign individual impairment, (2) create composite scores from multiple neurocognitive tests, and (3) assess the clinical relevance of raw scores.

To address this need, we propose to enroll and collect data in healthy HIV-seronegative controls at ACTG non-U.S. sites for the neurocognitive battery implemented in A5199. These data will serve as a foundation for future normative data in these settings, and we expect this data to be utilized for many years to come. The data will also provide a foundation for the assignment of individual impairment.

3.0 STUDY DESIGN

Study participants will be administered neuropsychological tests that include Timed Gait, Finger Tapping (Dominant and non-Dominant), Grooved Pegboard (Dominant and non-Dominant), Semantic Verbal Fluency, and WAIS-R Digit Symbol test. In addition, the Hopkins Verbal Learning Test-Revised (HVLT-R) with delayed recall, Color Trails, and the International HIV Dementia Scale (IHDS) will be administered. These neuropsychological tests covered the five domains stipulated in the NIMH-sponsored diagnostic criteria revision from Antinori [19]:

Fluency (Semantic Verbal Fluency) Executive Functions (Color Trails –II) Speed of Information Processing (Color Trails – I, WAIS-R Digit Symbol) Verbal Learning (HVLT-R); Verbal Memory (Delayed Recall) Motor Skills (Grooved Pegboard Test, Finger Tapping Test, Timed Gait).

An assessment of activities of daily living, quality of life, and psychosocial components will be also be included to assess functional deficits.

A subset of participants from each stratum will return for a follow-up visit in 6 months. These participants will be readministered the entry tests, and medical/medication assessments will be conducted to ensure continued normal neurological functioning without intervening events.

4.0 SELECTION AND ENROLLMENT OF PARTICIPANTS

4.1 Step 1: Inclusion Criteria

4.1.1 Absence of HIV-1 infection, as documented by a negative result of any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit within 30 days of study entry.

NOTE: The term “licensed” refers to a kit that has been certified or licensed by an oversight body within that country and validated internally.

4.1.2 Presented for HIV testing, at any location, within the last 30 days.


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4.1.3 Normal developmental history.

4.1.4 Karnofsky performance score 90 within 15 days prior to study entry.

4.1.5 Men and women age 18 years at study entry.

4.1.6 Ability to provide the number of completed years of education.

4.1.7 Ability and willingness of participant to provide informed consent.

4.2 Step 1: Exclusion Criteria

4.2.1 Prior antiretroviral therapy.

4.2.2 Current illness that in the opinion of the investigator is likely to have an impact on neurological or neurocognitive functioning.

4.2.3 Current use of medication that in the opinion of the investigator is likely to alter mental status or neurocognitive functioning including, but not limited to, sedative hypnotics, benzodiazepines, opioid analgesics, barbiturates, antipsychotics, or anticholinergics.

4.2.4 History of physical illness or neurological, psychiatric, or developmental disorder that in the opinion of the investigator is likely to have an impact on the participant’s neurocognitive functioning, including, but not limited to, dementia, neurosyphilis, CNS tuberculosis, CNS mass lesions, stroke, epilepsy, head trauma, or transient ischemic attack.

4.2.5 Active drug or alcohol use or dependence that interferes with social interactions, work, or other areas of functioning.

4.2.6 Serious illness requiring systemic treatment and/or hospitalization within 15 days prior to study entry.

4.2.7 Employment at the ACTG research clinic.

4.3 Step 2: Inclusion Criteria

4.3.1 Absence of HIV-1 infection, as documented by a negative result from any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit within 30 days of Step 2 enrollment.

NOTE: The term “licensed” refers to a kit that has been certified or licensed by an oversight body within that country and validated internally.

4.3.2 Completed Step 1 registration, assessments, and evaluations.

4.3.3 Willingness and ability to complete a second visit.


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4.4 Step 2: Exclusion Criteria

4.4.1 Since Step 1 study visit, physical, neurological, or psychiatric illness, that in the opinion of the investigator is likely to have an impact on the participant’s neurocognitive functioning, including, but not limited to dementia, neurosyphilis, CNS tuberculosis, CNS mass lesions, stroke, epilepsy, head trauma, or transient ischemic attack.

4.4.2 Active drug or alcohol use or dependence that interferes with social interactions, work, or other areas of functioning.

4.4.3 Serious illness requiring systemic treatment and/or hospitalization within 15 days prior to Step 2 entry.

4.4.4 Current use of medication that in the opinion of the investigator is likely to alter mental status or neurocognitive functioning including, but not limited to, sedative hypnotics, benzodiazepines, opioid analgesics, barbiturates, antipsychotics, or anticholinergics.

4.4.5 Employment at the ACTG research clinic.

4.5 Participant Recruitment

In an effort to facilitate study enrollment and ensure a broad range of participants, the A5271 team requires that each site submit a site implementation plan (SIP). The SIP must be approved by the A5271 team prior to the site completing protocol registration. Please refer to the A5271 Manual of Operations (MOPS) for the SIP template to be followed.

The SIP will need to detail the process by which the site staff will identify, approach, and recruit individuals who are potential candidates for A5271. In order to recruit volunteers who mirror the economic, cultural, and risk factor epidemiology of the local HIV at-risk population, sites are limited to enrolling those who have recently presented for HIV testing. The volunteers may present for testing at their local health clinic, voluntary counseling and testing (VCT) center, or any other testing site. The A5271 team suggests the use of institutional review board/ethics committee (IRB/EC)-approved flyers in local health care clinics, hospitals, and VCT centers.

Sites are required to establish a relationship with the local VCT center. This relationship will allow for recruitment of HIV-negative individuals and serve as a direct referral of participants who have recently tested HIV-negative. Sites will have to identify the local VCT center in the SIP.

4.6 Study Enrollment Procedures

4.6.1 Prior to implementation of this protocol, and any subsequent full version amendments, each site must have the protocol and the protocol informed consent form(s) approved, as appropriate, by their local institutional review board


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(IRB)/ethics committee (EC) and any other applicable regulatory entity (RE). Upon receiving final approval, sites will submit all required protocol registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). The DAIDS PRO will review the submitted protocol registration packet to ensure that all of the required documents have been received. Protocol activation is required prior to enrolling participants into the study. Prior to protocol activation, the site must have their SIP approved by the study team. The SIP is located in the A5271 MOPS on the PSWP. Completed SIPs can be submitted to the team at [email protected].

Site-specific informed consent forms (ICFs) WILL NOT be reviewed or approved by the DAIDS PRO, and sites will receive an Initial Registration Notification when the DAIDS PRO receives a complete registration packet. Receipt of an Initial Registration Notification indicates successful completion of the protocol registration process. Sites will not receive any additional notifications from the DAIDS PRO for the initial protocol registration. A copy of the Initial Registration Notification should be retained in the site's regulatory files.

Upon receiving final IRB/EC and any other applicable RE approvals for an amendment, sites should implement the amendment immediately. Sites are required to submit an amendment registration packet to the DAIDS PRO at the RCC. The DAIDS PRO will review the submitted protocol registration packet to ensure that all the required documents have been received. Site-specific ICF(s) WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS PRO receives a complete registration packet. A copy of the Amendment Registration Notification should be retained in the site's regulatory files.

For additional information on the protocol registration process and specific documents required for initial and amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual.

4.6.2 Participant Registration

For participants from whom informed consent has been obtained, but who are deemed ineligible or who do not enroll into Step 1, an ACTG Screening Failure Results form must be completed and keyed into the database.

Participants who meet eligibility criteria for A5271 will be enrolled according to standard ACTG DMC procedures. At Step 1, study participants will be offered the option of a single 6-month follow-up visit.

Participants who volunteer to return and complete a 6-month follow-up visit (800 total participants comprising 10 from each stratum) will be registered to Step 2 when they return for the second study visit in 6 months according to standard ACTG DMC procedures. Participants who meet the requirements for Step 2 will register according to standard ACTG DMC procedures.



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4.7 Coenrollment

Coenrollment into other ACTG and non-ACTG studies will be considered on an individual basis. For specific questions and approval regarding coenrollment, e-mail the A5271 CMC ([email protected]).

5.0 STUDY TREATMENT

This is an observational study. No study treatment will be administered through A5271.



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6.0 CLINICAL AND LABORATORY EVALUATIONS

6.1 Schedule of Events (SOE)

Evaluation Screening Step 1 Entry

Step 2 Interim Contacts

6-month Follow-up

Visit(-15/+45

days)

Step 1 Entry + 3 Months

(+/- 4 weeks)

14 Days prior to 6-month

Follow-up Visit

(+/- 3 days)Documentation of HIV-1 Negative Serostatus X X

HIV-1 Testing X

Demographics XMedical History/Medical History Update X X X

Karnofsky Performance X X

Neurological Examination X X

BMI X X

Clinical Assessments X X

Current Medications X X XNeuropsychological Examination X X

Functional Assessment X XQuality of Life/Psychosocial Interview

X X

Participant Contact X X

6.2 Timing of Evaluations

6.2.1 Screening Evaluations

Screening evaluations to determine eligibility must be completed no more than 15 days prior to study entry, unless otherwise stated.


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In addition to data collected on participants who enroll into this study, demographic, clinical, and laboratory data on screening failures will be captured in a screening log and entered into the ACTG database.

6.2.2 Step 1 Entry Evaluations

Entry evaluations must occur after study screening evaluations. The screening and entry evaluations can be completed at one study visit.

6.2.3 Interim Contact

Interim contact with study participants who will be completing Step 2 must be conducted according to the SOE.

6.2.4 Step 2 Evaluations (Follow-up)

Follow-up evaluations must occur 180 days after the entry evaluations, -15/+45 days.

If a rapid HIV test is completed, the testing and Step 2 procedures may occur on the same day. If an ELISA or E/CIA test is completed, the testing and procedures will have to occur on separate visits, pending the results of the test. The Step 2 study visit must be completed within 30 days of the HIV testing.

6.2.5 Off-Study Evaluation

Step 1 participants who do not complete entry evaluations or Step 2 participants who do not complete the 6-month evaluations must have their off-study case report forms (CRFs) completed and keyed.

6.3 Instructions for Evaluations

All clinical and laboratory information required by this protocol is to be present in the source documents. Sites must refer to the Source Document Guidelines on the DAIDS Web site for information about what must be included in the source document: http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/SourceDocAppndx.pdf

All evaluations are to be recorded on the CRF and keyed into the database unless otherwise specified.

Participants should be asked to bring all available medical history and medication history with them for the study visit(s).

6.3.1 Documentation of HIV-1 Negative Serostatus

Absence of HIV-1 infection, as documented by ELISA, EIA, or any rapid test kit, within 30 days prior to study entry. HIV-1 testing will not be completed as part of the study at screening. Please refer to section 4.1.1 regarding assay

http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/SourceDocAppndx.pdf

http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/PDF/SourceDocAppndx.pdf


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requirements.

Participants are required to have written documentation of HIV-1 negative serostatus for both the entry visit and the follow-up visit.

6.3.2 HIV-1 Testing

Absence of HIV-1 infection within 30 days prior to the Step 2 6-month follow-up visit. Please refer to section 4.3.1 regarding assay requirements. HIV-1 testing will be completed as part of the study at the Step 2 follow-up visit. A participant’s serostatus is indicated within the eligibility checklist.

Each site is required to have a referral process in place for participants who test HIV positive at the 6-month follow-up. This will be a site-specific plan that will include referral to the partner VCT center. This plan must be included in each site’s SIP. The SIP must be approved by the A5271 team prior to protocol registration. Please refer to the A5271 MOPS for the SIP template.

6.3.3 Demographics

Participant demographics, including education history, will be collected per the SOE.

NOTE: Participant demographics are based on participant self-report.

6.3.4 Medical History/Medical History Update

A medical history (including tuberculosis and malaria) must be collected at screening, recorded on a CRF, and keyed into the database at study entry. At study entry, record all signs/symptoms that occurred within 30 days prior to study entry on the CRF. A medical history update must be completed at the 6-month follow-up visit.

6.3.5 Karnofsky Performance Score

Participants’ functional capabilities are to be rated according to the Karnofsky Performance Scale and recorded on a CRF and keyed into the database.

6.3.6 Neurological Examination

A neurological examination must be performed by a physician or an appropriately trained mid-level health professional.

The results of the neurological examination must be recorded on the CRF and keyed into the database.


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6.3.7 Body Mass Index Calculation

Calculated body mass index (BMI) is to be collected at study entry and repeated at the 6-month follow-up visit. Calculate BMI using the following formula:

BMI = mass (kg)/ (height (m2))

The body mass index is to be recorded on the CRF.

6.3.8 Clinical Assessments

Targeted Diagnoses ChecklistAll diagnoses must be recorded on the Neurological Diagnoses CRF and keyed into the database.

DiagnosesAll diagnoses identified by the ACTG criteria for clinical events and other diseases must be recorded on CRFs and keyed into the database. Use the appropriate appendix listed on the CRF.

Signs and SymptomsAll associated signs, symptoms, laboratory results, or diagnostic test results observed or performed as part of establishing a diagnosis must be recorded on the CRF and keyed into the database, regardless of grade.

6.3.9 Current Medications

According to the SOE, all current prescription medications (with start and stop dates) are to be recorded on a CRF. Current non-prescription, alternative, and traditional medications are recorded in the source documents and reported as Yes/No on a CRF and keyed into the database.

6.3.10 Neuropsychological Examination

For a detailed explanation of the Brief Neuropsychological Examination, please refer to the A5271 MOPS.

The neuropsychological examination is weighted towards motor and speed of information processing. Training for the neuropsychological battery will be provided to the sites.

The neuropsychological examination includes the following tests:

Timed Gait: Timed gait is an assessment of gross motor functioning. Participants are timed on walking down a 10-yard (9.14 meter) course and returning. Total time for the test: About 3 minutes.


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Grooved Pegboard: Grooved pegboard is a timed test of fine motor skills. Participants are instructed to fill 25 holes with slotted pegs that have to be oriented to fit. Both dominant and nondominant hands are assessed.Total time for the test: About 10 minutes.

Finger Tapping: Finger tapping is a timed task of fine motor skill. Participants are instructed to depress a key as many times as possible in 10 second trials. Both dominant and nondominant hands are assessed. Total time for the test: About 5 minutes.

Semantic Verbal Fluency (Category Fluency): Semantic Verbal Fluency is a timed task requiring production of words in a specific category. Memory, speed of processing, initiation, and inhibition are assessed. This task does not require motor skills. Participants are given 60 seconds to produce as many words as possible within a specific category. The categories of animals will be used for visit 1 and clothing for the 6-month follow-up visit. Total time for the test: About 3 minutes.

Color Trails 1 and 2: These are tests of speed for attention, sequencing, mental flexibility, and visual search and motor function. The tests are paper and pencil based. Color Trails 1 requires the participant to rapidly connect encircled numbers scattered on a page in sequence from 1 to 25. In Color Trails 2, each number is presented twice, once with a pink background and once with a yellow background, and on this part the participant rapidly connects encircled numbers in sequence, but alternates between pink and yellow colors.Total time for the test: About 8 minutes.

HVTL-R: The HVLT-R provides information on the ability to learn and immediately recall verbal information across trials, as well as the ability to recall and recognize this information after a delay. A list of 12 words (four words from each of three semantic categories) is presented to the participant over three trials. After each trial, the participant is asked to recall as many items as possible from the list in any desired order. A 20-minute delay follows the administration of the three trials, after which the participant is asked to recall the list. Participants are then read a list of 24 words, one at a time, and are asked if the word appeared in the original list. The items presented during the recognition phase contain the originally presented words, words in the same semantic class, and unrelated words. In order to minimize practice effects that may result from repeated administrations, six alternate forms of the test are available. There is no time limit on this test. Total time for test: about 10 minutes

IHDS:The IHDS is a brief screening test for HIV dementia that provides information about verbal memory, motor, and psychomotor speed performance. It has three components: 1) four word memory recall, 2) finger tapping with the nondominant hand, and 3) an alternating hand sequence test with the nondominant hand. Total time for the test: about 3 minutes.


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6.3.11 Functional Assessment

Activities of daily living assessment interview will be completed as part of the neurological exam Activities of Daily Living (ADL) form (revision of Lawton and Brody ADL).

6.3.12 Quality of Life/Psychosocial Interview

Health Alcohol and drug use

6.3.13 Participant Contact

The site staff must have interim contact with each participant selected to have a Step 2 6-month follow-up visit to remind them of their appointment. The site’s interim contact with a participant must be documented in the participant’s source documents.

If a site is not able to contact the participant, documentation of all efforts to reach the person must be included in the participant’s source documents.

Sites are encouraged to collect alternative contacts, such as parents or relatives, who would know the whereabouts of the participant in case the person has changed residence prior to follow-up.

7.0 CLINICAL MANAGEMENT ISSUES

As an observational study, there is limited clinical management. However, if at any screening or on-study visit, a medical, including positive HIV test results, or neurological abnormality is identified, the participant will be referred to local care for follow-up.

NOTE: Prior to enrolling their first participant, A5271 participating sites must have a referral process in place.

8.0 CRITERIA FOR DISCONTINUATION

8.1 Premature Study Discontinuation

Failure by the participant to attend clinic visits or complete evaluations. Positive HIV test (for Step 2 participants). Request by the participant to withdraw. At the discretion of the ACTG, local IRBs/ECs, other in-country regulatory agencies,

U.S. Office for Human Research Protections (OHRP), National Institute of Allergy and Infectious Diseases (NIAID), or investigator.


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9.0 STATISTICAL CONSIDERATIONS

9.1 General Design Issues

A5271 is an observational trial to collect data to estimate the distribution of neuropsychological responses in neurologically healthy HIV-seronegative individuals in resource-limited settings. Participants will be screened for good health using a neurological exam, a HIV serostatus exam, a detailed history, and assessments of functional status. Enrollment will be stratified by site (10 sites), sex, age (<35 years vs. ≥35 years), and years of education (<10 years vs. ≥10 years) for a total of 80 strata. Currently, comparative data on neurologically healthy individuals do not exist in resource-limited settings. Data collected in this study will be used as a reference standard for interpreting future neuropsychological data from countries represented by the sites. These data will primarily be helpful in making group comparisons between other populations and neurologically healthy individuals. These data should be used with caution when assessing individual diagnoses since more data may be required for reliable diagnosis.

Participants will be administered a superset of neuropsychological tests that include Timed Gait, Finger Tapping (Dominant and Nondominant), Grooved Pegboard (Dominant and Nondominant), Semantic Verbal Fluency, the International HIV Dementia Scale (IHDS), and WAIS-R Digit Symbol test. In addition, the Hopkins Verbal Learning Test-Revised and Color Trails will be administered. These tests cover the five domains stipulated in the NIMH-sponsored diagnostic criteria revision from Antinori et al. [19]: Fluency (Semantic Verbal Fluency); Executive Functions (Color Trails –II); Speed of Information Processing (Color Trails – I, WAIS-R Digit Symbol); Verbal Learning (Hopkins Verbal Learning Test- Revised); Verbal Memory (HTVL-R Delayed Recall); Motor Skills (Grooved Pegboard Test, Finger Tapping Test, Timed Gait). An assessment of activities of daily living will be included to assess functional deficits.

A subset of 800 participants (10 from each stratum) will have a 6-month follow-up neuropsychological testing, to estimate practice effects. At the follow-up visit, these participants will be administered a medical history evaluation to ensure continued normal neurological functioning and no intervening illnesses or substance abuse.

9.2 Endpoints

9.2.1 Primary Endpoints

Responses to neuropsychological tests:

Timed Gait (average time for three trials) Finger Tapping (average number of taps for the dominant and nondominant

hands) Grooved Pegboard (seconds to complete the dominant and nondominant

hands) Semantic Verbal Fluency (number of correct words)


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HVTL-R (number of words for the learning trials 1-3, the sum of the number of words for learning trials 1-3, number of words for the interference trial, number of words for delayed recall, number of correct and incorrect words for the recognition trial)

Color Trails 1 (number of seconds to complete) Color Trails 2 (number of seconds to complete) IHDS

9.2.2 Secondary Endpoints

Results of:

Functional assessment Quality of life assessment

Responses to neuropsychological tests at 6-month follow-up:

Timed Gait (average time for three trials) Finger Tapping (average number of taps for the dominant and nondominant

hands) Grooved Pegboard (seconds to complete the dominant and nondominant

hands) Semantic Verbal Fluency (number of correct words) HVLT-R (number of words for the learning trials 1-3, the sum of the number

of words for learning trials 1-3, number of words for delayed recall, number of correct and incorrect words for the recognition trial)

Color Trails 1 (number of seconds to complete) Color Trails 2 (number of seconds to complete) IHDS

9.3 Registration and Stratification

Participant enrollment in A5271 is stratified (80 strata), defined by site (10 sites), gender, age (<35 years vs. ≥35 years), and years of education (<10 years vs. ≥10 years). Thirty (30) participants per stratum will be enrolled. Each site will enroll 240 participants.

.At Step 1, study participants will be offered the option of a single 6-month follow-up visit. Ten participants per stratum will be registered to a follow-up visit (Step 2).

9.4 Sample Size and Accrual

It is desirable to estimate the true stratum-specific mean such that the 95% confidence interval (CI) for the mean is not wider than a 0.75 standard deviation (SD). Utilizing the t-distribution, 30 participants per stratum will result in a width of 0.746 (SD) for the 95% CI for the estimate of a stratum-specific mean.


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With 30 participants per stratum and 80 strata, the total sample size is 2400.

To estimate a site-specific practice effect with the same precision, 30 participants per strata per site would be required. Eighty participants per site will be enrolled into Step 2 (10 for each of 8 combination patterns defined by sex, age, and education levels), to account for the potential deletion of participants that drop out or that change neurological status over time.

9.5 Monitoring

A5271 is an observational study in which no treatment or intervention is provided. No formal interim analysis that includes hypothesis testing will be conducted. Furthermore participants are healthy HIV-seronegative individuals. Thus, limited interim monitoring for safety is required.

The statisticians and the data managers will prepare biannual administrative reports. These reports will include participant baseline information and will additionally examine protocol execution issues such as participant accrual by stratum, participant retention, baseline characteristics, endpoint evaluability, and data completeness. Details of the aforementioned reports will be described in the monitoring plan prepared by the statisticians and the data managers. The monitoring plan will be developed and distributed to the A5271 team for review and approval in collaboration with the A5271 protocol DAIDS medical officer.

9.6 Analyses

9.6.1 Primary Analyses

Descriptive statistics of the baseline responses to the neuropsychological tests will be summarized by stratum. These data will serve as unadjusted estimates of stratum-specific means and standard deviations within country. Histograms and box plots will be utilized to visually display the distributions.

However, pooling data across strata may result in more precise estimates. Within each site, a regression model will be constructed, modeling each neuropsychological response as a function of the age, sex, and education strata. First order and second order interactions will also be explored. A backwards elimination model-building strategy will be utilized to obtain adjusted estimates of parameters of interest. Model fit will be checked to ensure that the model is reasonable.

9.6.2 Secondary Analyses

For Step 2 participants, changes from baseline will be calculated. Descriptive statistics of the changes will be summarized by site for participants who did not have significant functional changes. These data will serve as unadjusted estimates of site-specific means and standard deviations within site. Histograms and box plots will be utilized to visually display the distributions of the changes.


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10.0 PHARMACOLOGY PLAN

There will be no pharmacology plan for A5271.

11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING

11.1 Records to Be Kept

CRF will be provided for each participant. Participants must not be identified by name on any CRFs. Participants will be identified by the PID and SID provided by the ACTG DMC.

11.2 Role of Data Management

11.2.1 Instructions concerning the recording of study data on CRFs will be provided by the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion.

11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized data for each ACTG study. This role extends from protocol development to generation of the final study databases.

11.3 Clinical Site Monitoring and Record Availability

11.3.1 Site monitors under contract to the NIAID will visit participating clinical research sites to review the individual participant records, including consent forms, CRFs, supporting data, laboratory specimen records, and medical records (physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of study participants, compliance with the protocol, and accuracy and completeness of records. The monitors also will inspect sites’ regulatory files to ensure that regulatory requirements are being followed.

The site investigator will make study documents (e.g., consent forms, CRFs) and pertinent hospital or clinic records readily available for inspection by the local IRB or ethics committee, the site monitors, the NIAID, and the OHRP for confirmation of the study data

11.4 Expedited Adverse Event Reporting to DAIDS

As an observational study, there will be no EAE reporting.

12.0 HUMAN SUBJECTS

12.1 Institutional Review Board (IRB) Review and Informed Consent

This protocol and the informed consent document (Appendix I) and any subsequent modifications will be reviewed and approved by the IRB or ethics committee responsible


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for oversight of the study. A signed consent form will be obtained from the participant. The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of the consent form will be given to the participant and this fact will be documented in the participant’s record.

12.2 Participant Confidentiality

All laboratory specimens, evaluation forms, reports, and other records that leave the site will be identified by coded number only to maintain participant confidentiality. All records will be kept locked. All computer entry and networking programs will be done with coded numbers only. Clinical information will not be released without written permission of the participant, except as necessary for monitoring by ACTG, IRB/EC, other in-country regulatory agencies, the NIAID, or the OHRP.

12.3 Study Discontinuation

The study may be discontinued at any time by the ACTG, IRB/EC, the NIAID, the OHRP, or other government agencies as part of their duties to ensure that research subjects are protected.

13.0 PUBLICATION OF RESEARCH FINDINGS

Publication of the results of this trial will be governed by ACTG policies.

14.0 BIOHAZARD CONTAINMENT

As the transmission of HIV and other blood-borne pathogens can occur through contact with contaminated needles, blood, and blood products, appropriate blood and secretion precautions will be employed by all personnel in the drawing of blood and shipping and handling of all specimens for this study, as currently recommended by the Centers for Disease Control and Prevention and the National Institutes of Health.All dangerous goods materials, including diagnostic specimens and infectious substances, must be transported using packaging mandated by CFR 42 Part 72. Please refer to instructions detailed in the International Air Transport Association (IATA) Dangerous Goods Regulations. .


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15.0 REFERENCES

1. World Health Organization. Global summary of the HIV/AIDS epidemic, December 2003. Geneva, Switzerland. World Health Organization, December, 2003.

2. American Academy of Neurology. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 1991;41(6):778-85.

3. Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. clinical features. Ann Neurol 1986;19:517-24.

4. Navia BA, Cho ES, Petito CK, Price RW. The AIDS dementia complex: Neuropathology. Ann Neurol 1986;19:525-35.

5. McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 1993;43(11):2245-52.

6. Robertson KR, Hall CD. HIV related mild cognitive impairment and AIDS dementia complex. Semin Neurol 1992;12(1):18-27.

7. Elder GA, Sever JL. AIDS and neurological disorders: an overview. Ann Neurol.1988;23:S4-S6.

8. Schifitto G., Kieburtz K., McDermott M, et al. Clinical trials in HIV associated cognitive impairment: Cognitive and functional domains. Neurology 2001;56:415-18.

9. Tozzi V, Balestra P, Galgani S, et al. Neurocognitive performance and quality of life in patients with HIV infection. AIDS Human Retrovir 2004;19(8):643-52.

10. Price RW, Sidtis JJ. Evaluation of the AIDS dementia complex in clinical trials. J AIDS 1990; 3(Supp 2):S51-60.

11. Sidtis JJ, Gatsonis C, Price RW, et al. Zidovudine treatment of the AIDS dementia complex: results of a placebo controlled trial. AIDS Clinical Trials Group. Ann Neurol 1993;33:343-9.

12. Robertson K for the ACTG 5199 team. Thailand baseline neurocognitive data from the International Neurological Study: ACTG 5199. Presented at the NeuroAIDS in Asia and the Pacific Rim, July 19-20, 2007; Sydney, Australia.

13. Heaton R, Cysique C. NeuroAIDS in China. Presented at the NeuroAIDS in Asia and the Pacific Rim, July 19-20, 2007; Sydney, Australia.


06/01/10REFERENCES (Cont'd)

14. Valcour V. Predicting cognitive improvement among patients initiating HAART in Bangkok, Thailand. Presented at the NeuroAIDS in Asia and the Pacific Rim, July 19-20, 2007; Sydney, Australia.

15 Marcotte T, NeuroAIDS in Pune, India. Presented at the NeuroAIDS in Asia and the Pacific Rim, July 19-20, 2007; Sydney, Australia.

16. Das Gupta J, Rao S, Satishchandra P, et al. Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India. J Neurovirol. 2007 Aug;13(4):397-8.

17. Robertson KR, Nakasujja N, Wong M, et al. Pattern of neuropsychological performance among HIV positive patients in Uganda. BMC Neurol. 2007 Apr 5;7:8N.

18. Wong MH, Robertson K, Nakasujja N, et al. Frequency of and risk factors for HIV dementia in an HIV clinic in sub-Saharan Africa. Neurology. 2007;68(5):350-5.

19. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-99.

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APPENDIX I

DIVISION OF AIDSAIDS CLINICAL TRIALS GROUP (ACTG)

SAMPLE INFORMED CONSENTFor protocol: A5271

Collection of Comparison Neurocognitive Data in Resource-Limited Settings A5271, FINAL Version 1.0, dated 06/01/10

SHORT TITLE FOR THE STUDY: Collection of Neurocognitive Data

INTRODUCTION

You are being asked to take part in a research study. This study is sponsored by the National Institutes of Health. The investigator in charge of this study at this site is: (insert name of Principal Investigator). Before you decide if you want to be a part of this study, we want you to know about the study.

This is a consent form. It gives you information about this study. The study staff will talk with you about this information. You are free to ask questions about this study at any time. If you agree to take part in this study, you will be asked to sign this consent form. You will get a copy to keep.

WHY IS THIS STUDY BEING DONE?

The purpose of this study is to find out how many people have problems with remembering, learning, or with activities of daily living, such as if you need help completing tasks like getting dressed. The information gained from this study will be compared to information from other studies.

WHAT DO I HAVE TO DO IF I AM IN THIS STUDY?

Screening

If you decide to enroll in this study and sign this consent form, you will be interviewed to make sure that you qualify. You also must have had a negative HIV test in the past 30 days in order to join this study. You will be asked questions about your medical history and the medications you currently take or have taken in the past.

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If you do not enroll into the study

If you decide not to take part in this study or if you do not meet the eligibility requirements, we will still use some of your information. As part of this screening visit, some demographic (e.g., age, gender, race), clinical (e.g., disease condition, diagnosis), and laboratory (e.g., HIV status) information is being collected from you so that ACTG researchers may help determine whether there are patterns or common reasons why people do not join a study.

Study Entry Visit

The screening and entry visit may be on different days or on the same day. During the study entry visit you will be asked about your health, how you have been feeling, and any medications you may be taking. You will also be asked about how your daily activities are going and any alcohol or drugs you may use. You will have your height and weight taken.

You will have a neurological exam. The neurological exam will see if you have any nerve damage or nervous system problems and will take about 30 to 45 minutes.

You will take neuropsychological tests. During the neuropsychological tests you will answer questions, list items (such as naming foods, or animals, or some other groups you know), do simple tasks, and see how long it takes you to walk a short distance. These tests will take about 1 hour.

You will not receive the results of either the neurological exam or the neuropsychological tests.

On-Study Evaluations

If you agree, you will be offered the option to have an additional study visit about 6 months after the study entry visit. Approximately 800 out of a total of 2400 study participants will have a second study visit after six months.

6 month Follow-up Visit

If you choose to have a study follow-up visit, study staff will contact you twice to remind you of your appointment. You will return to the clinic approximately 6 months after your study entry visit. You will have a blood, urine, or mouth swab test to determine if you have been infected with HIV. If you have the blood test, you will have a fingerstick done, or approximately 1 teaspoon of blood will be drawn from a vein in your arm. If you test negative for HIV, you will have all the same evaluations listed under “Study Entry Visit”. If the test is positive, you will be referred for another test to confirm if you are infected with HIV and you will be taken off study. If the second test is positive for HIV, you will be referred to an appropriate health care practitioner for care for HIV. This visit may take up to three hours.

HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?

About 2400 people will take part in this study.

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HOW LONG WILL I BE IN THIS STUDY?

1600 participants will be on the study for 1 study visit only. 800 participants will have a follow-up visit and will be on the study for 6 months.

WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY?

The study doctor may need to take you off the study early without your permission if:

the study is cancelled by the ACTG, National Institutes of Health, the Office for Human Research Protections (OHRP), the site’s Institutional Review Board or ethics committee (IRB/EC), or other in-country regulatory agencies. (An IRB/EC is a committee that watches over the safety and rights of research subjects.)

you are not able to attend the study visits as required by the study

WHAT ARE THE RISKS OF THE STUDY?

This is a study with limited risk involved.

Risks associated with having your blood drawn include: Discomfort associated with the needle piercing your skin Dizziness/feeling lightheaded, and/or fainting Bleeding or bruising at the spot where the needle enters your body Infection at site of puncture

There is a minimal risk of potential frustration or embarrassment from completing the neuropsychological tests.

There is also potential social risks/stigma, embarrassment and anxiety that might arise from a positive HIV test result.

ARE THERE BENEFITS TO TAKING PART IN THIS STUDY?

If you take part in this study, you will receive no direct benefit from the study apart from a free examination. Information learned from this study may help others.

WHAT ABOUT CONFIDENTIALITY?

Efforts will be made to keep your personal information confidential. We cannot guarantee absolute confidentiality. Your personal information may be disclosed if required by law. Any publication of this study will not use your name or identify you personally.

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Your records may be reviewed by the ACTG, OHRP, (insert name of site) IRB/EC, National Institutes of Health (NIH), study staff, and study monitors.

WILL I RECEIVE ANY PAYMENT?

[This section will include information on any planned reimbursement or payment to the participant.]

WHAT HAPPENS IF I AM INJURED?

If you are injured as a result of study related procedures, you will be given immediate treatment for your injuries. The cost for this treatment will be charged to you. There is no program for compensation either through this institution or the National Institutes of Health. You will not be giving up any of your legal rights by signing this consent form.

WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT?

Taking part in this study is completely voluntary. You may choose not to take part in this study or leave this study at any time. Your decision will not have any impact on your participation in other studies conducted by National Institutes of Health (NIH) and will not result in any penalty or loss of benefits to which you are otherwise entitled.

We will tell you about new information from this or other studies that may affect your health, welfare, or willingness to stay in this study. If you want the results of the study, let the study staff know.

WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS?

For questions about this study or a research-related injury, contact:

name of the investigator or other study staff telephone number of above

For questions about your rights as a research subject, contact:

name or title of person on the Institutional Review Board (IRB) or other organization appropriate for the site

telephone number of above

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SIGNATURE PAGE

If you have read this consent form (or had it explained to you), all your questions have been answered and you agree to take part in this study, please sign your name below.

___________________________ _________________________________________Participant’s Name (print) Participant’s Signature and Date

____________________________ _________________________________________Participant’s Legal Guardian (print) Legal Guardian’s Signature and Date(As appropriate)

____________________________ _________________________________________Study Staff Conducting Study Staff’s Signature and DateConsent Discussion (print)

____________________________ _________________________________________Witness’s Name (print) Witness’s Signature and Date(As appropriate)

6-month follow-up visit:If you have read this consent form (or had it explained to you), all your questions have been answered and you agree to take part in the 6-month follow-up visit, please sign your name below.

___________________________ _________________________________________Participant’s Name (print) Participant’s Signature and Date

____________________________ _________________________________________Participant’s Legal Guardian (print) Legal Guardian’s Signature and Date(As appropriate)

____________________________ _________________________________________Study Staff Conducting Study Staff’s Signature and DateConsent Discussion (print)

____________________________ _________________________________________Witness’s Name (print) Witness’s Signature and Date(As appropriate)

a____ · web viewsites registering to this study must contact the computer support group at the...

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